US5346921A - Treatment of inflammation with 15-keto-prostaglandin compounds - Google Patents

Treatment of inflammation with 15-keto-prostaglandin compounds Download PDF

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US5346921A
US5346921A US07/972,092 US97209292A US5346921A US 5346921 A US5346921 A US 5346921A US 97209292 A US97209292 A US 97209292A US 5346921 A US5346921 A US 5346921A
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Ryuji Ueno
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Sucampo GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a treatment of inflammatory diseases with a 15-ketoprostaglandin compound.
  • Prostaglandins are members of a class of organic carboxylic acid that are contained in human and most other mammalian tissues or organs and that exhibit a wide range of physiological activities.
  • Some synthetic analogues have somewhat modified skeletons.
  • the primary PGs are classified based on the structural feature of the five-membered cycle moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs, and also on the presence or absence of unsaturation and oxidation in the chain moiety as:
  • PGFs are sub-classified according to the configuration of hydroxy group at 9 into ⁇ (hydroxy group being in the alpha configuration) and ⁇ (hydroxy group being in the beta configuration).
  • PGE 1 , PGE 2 and PGE 3 are known to have vasodilating, hypotensive, gastro-juice reducing, intestine-hyperkinetic, uterine contracting, diuretic, bronchodilating and anti-ulcer activities. Also, PGF 1 ⁇ , PGF 2 ⁇ and PGF 3 ⁇ are known to have hypertensive, vasocontracting, intestine-hyperkinetic, uterine contracting, luteo-regressive and bronchocontracting activities.
  • 15-keto i.e. having an oxo group at position 15 in place of the hydroxy group
  • 1314-dihydro-15-ketoprostaglandins are known as substances naturally produced by enzymatic actions during metabolism of primary PGs (Acta Physiologica Scandinavica, 66., 509, 1966). It has also been described that 15-ketoprostaglandin F 2 ⁇ has an antipregnant activity.
  • 15-ketoprostaglandin compounds are useful as an agent for treating inflammatory diseases.
  • the present invention provides a method for treatment of inflammatory diseases which comprises administering, to a subject in need of such treatment, an anti-inflammatorily effective amount of a 15-ketoprostaglandin compound.
  • the present invention provides a use of a 15-ketoprostaglandin compound for the manufacture of a medicament for treatment of inflammatory diseases.
  • the present invention provides a pharmaceutical composition for treatment of inflammatory diseases comprising a 15-ketoprostaglandin compound in association with a pharmaceutically acceptable carrier, diluent or excipient.
  • inflammatory disease means lesions caused by a defensive reaction or an inflammatory reaction of a living body against harmful influence of circumstances (such as physical, chemical and biological circumstances) having signs of redness, heat, pain, swelling and loss of function.
  • anti-inflammatory means a tendency or an ability to act against or protect from or inhibit the inflammatory reaction.
  • the 15-keto-prostaglandin compounds used in the instant invention have such tendency or ability.
  • treatment refers to any means of control of a disease in a mammal, including preventing the disease, curing the disease, relieving the disease and arresting or relieving the development of the disease.
  • 15-ketoprostaglandin compounds include any prostaglandin derivatives which have an oxo group in place of the hydroxy group at position 15 of the prostanoic acid nucleus irrespective of the presence or absence of the double bond between positions 13 and 14.
  • Nomenclature of 15-keto-PG compounds herein uses the numbering system of prostanoic acid represented in formula (A) shown above.
  • formula (A) shows a basic skeleton having twenty carbon atoms
  • the 15-keto-PG compounds used in the present invention are not limited to those having the same number of carbon atoms.
  • the carbon atoms in Formula (A) are numbered 2 to 7 on the ⁇ -chain starting from the ⁇ -carbon atom adjacent to the carboxylic carbon atom which is numbered 1 and towards the five-membered ring, 8 to 12 on the said ring starting from the carbon atom on which the ⁇ -chain is attached, and 13 to 20 on the ⁇ -chain starting from the carbon atom adjacent to the ring.
  • PGDs, PGEs and PGFs have a hydroxy group on the carbon atom at position 9 and/or 11 but in the present specification the term "15-keto-PG compounds" includes PGs having a group other than a hydroxyl group at position 9 and/or 11. Such PGs are referred to as 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PG compounds.
  • 15-keto-PG compounds are based upon the prostanoic acid. These compounds, however, can also be named according to the IUPAC naming system.
  • 13,14-dihydro-15-keto16R,S-fluoro-PGE 2 is (Z)-7- ⁇ (1R,2R,3R)-3-hydroxy-2-[(4R,S)-4-fluoro-3-oxo-1-octyl]-5-oxocyclopentyl ⁇ hept-5-enic acid.
  • 13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE 2 methyl ester is methyl 7- ⁇ (1R,2S,3S)-3-methyl-2-[3-oxo-1-decyl]-5-oxo-cyclopentyl ⁇ -hept-5-enoate.
  • 13,14-dihydro-6,15-diketo-19-methyl-PGE 2 ethyl ester is ethyl 7- ⁇ (1R,2S,3S)-3-hydroxy-2-(7-methyl-3-oxo-1-octyl)-5-oxo-cyclopentyl ⁇ -6-oxo-heptanoate.
  • 13,14-dihydro-15-keto-20-ethyl-PGF 2 ⁇ isopropyl ester is isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxo-1-decyl)-cyclopentyl]-hept-5-enoate.
  • 13,14-dihydro-15-keto-20-methyl-PGF 2 ⁇ methyl ester is methyl (Z)-7-[(1R,2R,3R,5S)-3,5- dihydroxy-2- ⁇ 3-oxo-1-nonyl ⁇ -cyclopentyl]-hept-5-enonate.
  • the 15-keto-PG compounds used in the present invention may be any derivatives of PG insofar as they have an oxo group at position 15 in place of the hydroxy group, and may have a double bond between positions 13 and 14 (15-keto-PG subscript 1 compounds), two double bonds between positions 13 and 14 as well as positions 5 and 6 (15-keto-PG subscript 2 compounds), or three double bonds between positions 13 and 14, positions 5 and 6 as well as positions 17 and 18 (15-keto-PG subscript 3 compounds), and may have a single bond between positions 13 and 14 (13,14-dihydro-15-keto-PG compounds).
  • Typical examples of the compounds used in the present invention are 15-keto-PG subscript 1, 15-keto-PG subscript 2, 15-keto-PG subscript 3, 13,14-dihydro-15-keto-PG subscript 1, 13,14-dihydro-15-keto-PG subscript 2, and 13,14-dihydro-15-keto-PG subscript 3, wherein PG is as defined above as well as their derivatives.
  • substitution products or derivatives include esters at the carboxy group at the alpha chain, pharmaceutically or physiologically acceptable salts, unsaturated derivatives having a double bond or a triple bond between positions 2 and 3 or positions 5 and 6, respectively, substituted derivatives having substituent(s) on carbon atom(s) at position 3, 5, 6, 16, 17, 19 and/or 20 and compounds having lower alkyl or a hydroxy (lower) alkyl group at position 9 and/or 11 in place of the hydroxy group, of the above PGs.
  • Substituents on the carbon atom at position 3, 17 and/or 19 include lower alkyl, for example, C 1-4 alkyl, especially methyl and ethyl.
  • Substituents on the carbon atom at position 16 include lower alkyl e.g. methyl, ethyl etc., hydroxy and halogen atom e.g. chlorine, fluorine, aryloxy e.g. trifluoromethylphenoxy, etc.
  • Substituents on the carbon atom at position 17 include halogen atom e.g. chlorine, fluorine, etc.
  • Substituents on the carbon atom at position 20 include saturated and unsaturated lower alkyl e.g. C 1-4 alkyl, lower alkoxy e.g. C 1-4 alkoxy and lower alkoxy (lower) alkyl e.g. C 1-4 alkoxy-C 1-4 alkyl.
  • Substituents on the carbon atom at position 5 include halogen atom e.g. chlorine, fluorine, etc.
  • Substituents on the carbon atom at position 6 include oxo group forming carbonyl.
  • Stereochemistry of PGs having hydroxy, lower alkyl or lower (hydroxy) alkyl substituent on the carbon atom at position 9 and/or 11 may be alpha, beta or mixtures thereof.
  • Said derivatives may have an alkoxy, phenoxy or phenyl group at the end of the omega chain where the chain is shorter than the primary PGs.
  • Especially preferred compounds are those having a lower alkyl e.g. methyl, ethyl etc., a halogen atom e.g. chloro, fluoro etc. at position 16, those having a halogen atom e.g. chloro, fluoro etc. at position 17, those having a lower alkyl e.g. methyl, ethyl etc. at position 19, those having a halogen atom e.g. chloro, fluoro etc. at position 5, those having an oxo group at position 6, those having a lower alkyl, e.g. methyl, ethyl, etc. at position 20 and those having phenyl or phenoxy which are optionally substituted with halogen or haloalkyl at position 16 in place of the rest of the alkyl chain.
  • a group of preferred compounds used in the present invention has the formula ##STR2## wherein X and Y are hydrogen, hydroxy, halo, lower alkyl, hydroxy(lower)alkyl, or oxo, with the proviso that at least one of X and Y is a group other than hydrogen, and 5-membered ring may have at least one double bond, Z is hydrogen or halo, A is --CH 2 OH, --COCH 2 OH, --COOH or its functional derivative, B is --CH 2 --CH 2 , --CH ⁇ CH-- or --C ⁇ C--, R 1 is bivalent saturated or unsaturated, lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halo, oxo or aryl, R 2 is saturated or unsaturated, lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halo, hydroxy, oxo, lower alkoxy, lower alkanoyloxy, cyclo
  • Ra is hydrogen.
  • L and M are hydrogen atom, hydroxy, lower alkyl, hydroxy(lower)alkyl or oxo, provided that at least one of L and M is not hydrogen atom and that the five-membered ring may have one or two double bonds,
  • Q 1 ' and Q 2 ' are hydrogen atom, halogen atom or lower alkyl
  • D is --CH 2 --CH 2 --, --CH ⁇ CH--, --C ⁇ C-- or --CO--CH 2 --,
  • E is --CH 2 --CH 2 -- or --CH ⁇ CH--
  • W is --CH 2 --CH 2 --CH 2 --, --CH ⁇ CH--CH 2 or --CH 2 --CH ⁇ CH--,
  • Ra' is hydrogen atom, lower alkyl, cyclo(lower)alkyl, monocyclic aryl, monocyclic aryl(lower)alkyl or monocyclic aroyl(lower)alkyl,
  • Rb' is single bond or lower alkylene
  • Rc' is lower alkyl which is unsubstituted or substituted with halogen, lower cycloalkyl which is unsubstituted or substituted with lower alkyl, monocyclic aryl which is unsubstituted or substituted with halogen or halo(lower)alkyl, or monocyclic aryloxy which is unsubstituted or substituted with halogen or halo(lower)alkyl,
  • R 1 is hydrogen atom
  • the term "unsaturated" in the definitions for R 1 and R 2 is intended to include at least one and optionally more than one double bond and/or triple bond isolatedly, separately or serially present between carbon atoms of main and/or side chain. According to usual nomenclature, an unsaturation between two serial positions is represented by denoting younger number of said two positions, and an unsaturation between two distal positions is represented by denoting both of the positions. Preferred unsaturation is a double bond at position 2 and a double or triple bond at position 5.
  • lower or medium aliphatic hydrocarbon residue refers to a straight or branched chain hydrocarboyl group having 1 to 14 carbon atoms (for a side chain, 1 to 3 carbon atoms being preferred) and preferably 2 to 8 carbon atoms for R 1 and 2 to 10 carbon atoms for R 2 .
  • halo denotes fluoro, chloro, bromo and iodo.
  • lower is intended to include a group having 1 to 6 carbon atoms unless otherwise specified.
  • lower alkyl as a group or a moiety in hydroxy(lower)alkyl includes saturated and straight or branched chain hydrocarbon radicals containing 1 to 6, preferably 1 to 5 and more preferable 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • lower alkoxy refers to the group lower-alkyl-O- wherein lower alkyl is as defined above.
  • lower alkylene refers to the group obtainable by removing a hydrogen atom from the lower alkyl group as defined above and includes e.g. methylene, ethylene, propylene, tetramethylene, 2-methyltetramethylene, pentamethylene, hexamethylene etc.
  • halo(lower) alkyl refers to lower alkyl group as defined above which is substituted with at least one and preferably 1 to 3 halogen atoms as defined above and includes e.g. chloromethyl, bromomethyl, fluoromethyl, trifluoromethyl, 1,2-dichloromethyl, 1,2,2-trichloroethyl, chloropropyl, chlorobutyl, chloropentyl, chlorohexyl etc.
  • hydroxy(lower)alkyl refers to alkyl as defined above and substituted with at least one hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.
  • lower alkanoyloxy refers to a group of the formula: RCO--O-- wherein RCO-- is an acyl group formed by oxidation of a lower alkyl group as defined above, e.g. acetyl.
  • cyclo(lower)alkyl refers to a cyclic group formed by cyclization of a lower alkyl group as defined above.
  • aryl includes unsubstituted or substituted aromatic carbocyclic or heterocyclic (preferably monocyclic) groups, e.g. phenyl, tolyl, xylyl and thienyl.
  • substituents are halo and halo(lower) alkyl wherein halo and lower alkyl being as defined above.
  • aryloxy refers to a group of the formula: ArO- wherein Ar is aryl as defined above.
  • monocyclic aryl includes phenyl unsubstituted or substituted with lower alkyl substituents, e.g phenyl, tolyl, xylyl, cumenyl etc.
  • m.Aro- monocyclic aryl as defined above and includes e.g. phenoxy, tolyloxy, cumenyloxy etc.
  • monocyclic aryl(lower)alkyl refers to a group consisting of monocyclic aryl and lower alkyl, both as defined above, combined together, and includes, for example, benzyl, phenethyl, tolylmethyl etc.
  • monocyclic aroyl(lower)alkyl refers to a group consisting of monocyclic aroyl such as benzoyl unsubstituted or substituted with lower alkyl substituent and lower alkyl as defined above combined together, and includes phenacyl(benzoylmethyl), toluoylmethyl, xyloylmethyl, etc.
  • the term "functional derivative" of carboxy as A includes salts (preferably pharmaceutically acceptable salts), esters and amides.
  • Suitable “pharmaceutically acceptable salt” includes conventional non-toxic salt, and may be a salt with an inorganic base, for example a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), ammonium salt, a salt with an organic base, for example, an amine salt (e.g.
  • methylamine salt dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)ethane salt, monomethylmonoethanolamine salt, procaine salt, caffeine salt, etc.), a basic amino acid salt (e.g. arginine salt, lysine salt, etc.), tetraalkylammonium salt and the like.
  • These salts can be prepared by the conventional process, for example from the corresponding acid and base or by salt interchange.
  • esters are aliphatic esters, for example, C 1-6 alkyl ester such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, 1-cyclopropylethyl ester, etc., lower alkenyl ester such as vinyl ester, allyl ester, etc., lower alkynyl ester such as ethynyl ester, propynyl ester, etc., hydroxy(lower) alkyl ester such as hydroxyethyl ester, lower alkoxy(lower)-alkyl ester such as methoxymethyl ester, 1-methoxyethyl ester, etc., and aromatic esters, for example, optionally substituted aryl ester such as phenyl ester, tolyl ester, t-butylphenyl ester, sal
  • amides are mono- or di- lower alkyl amides such as methylamide, ethylamide, dimethylamide, etc., arylamide such as anilide, toluidide, and lower alkyl- or aryl-sulfonylamide such as methylsulfonylamide, ethylsulfonylamide, tolylsulfonYlamide etc.
  • Preferred examples of A include --COOH, --COOCH 3 , --COOCH 2 CH 3 , --COOCH(CH 3 ) 2 and --CONHSO 2 CH 3 .
  • R 1 examples of preferred R 1 are --(CH 2 ) 2 --, --(CH 2 ) 6 --, --CH 2 CO(CH 2 ) 2 --, --CH 2 CH ⁇ CH(CH 2 ) 3 --, --CH 2 CO(CH 2 ) 4 --, --(CH 2 ) 2 CH ⁇ CH(CH 2 ) 2 --, --(CH 2 ) 4 CH ⁇ CH--, --CH 2 CH ⁇ C ⁇ CH(CH 2 ) 2 -- etc.
  • R 2 examples of preferred R 2 are --(CH 2 ) 2 CO(CH 2 ) 4 --CH 3 , --(CH 2 ) 2 CO(CH 2 ) 4 --COOH, --(CH 2 ) 2 COC(CH 3 ) 2 (CH 2 ) 3 --CH 3 , --(CH 2 ) 2 COCH 2 O-phenyl, --(CH 2 ) 2 COCH 2 O-methachlorophenyl, --(CH 2 ) 2 COCH2O-methatrifluorophenyl, --(CH 2 ) 2 COCH 2 O-3-thienyl, --(CH 2 ) 2 CO(CH 2 ) 2 -phenyl, --(CH 2 ) 2 COCH 2 CH(CH 3 )(CH 2 )CH 3 , --(CH 2 ) 2 COC(CH 3 ) 2 CH 2 OCH 2 CH 3 , --(CH 2 ) 2 COCH(CH ⁇ CH)(CH 2 ) 3 CH 3 , --(CH 2 ) 2 CO-cyclopenty
  • the configuration of the ring and ⁇ - and/or ⁇ -chain in the above formulas (I) and (II) may be the same as or different from that in the natural prostaglandins.
  • the present invention also include a mixture of a compound having natural configuration and that of unnatural configuration.
  • Examples of the typical compounds of the present invention are 15-keto-PGs and 13,14-dihydro-15-keto-PGs and their derivatives such as 6-oxo-derivatives, ⁇ 2 -derivatives, 3R,S-methyl-derivatives, 5R,S-fluord-derivatives, 5,5-difluoro-derivatives, 16R,S-methyl-derivatives, 16,16-dimethyl-derivatives, 16R,S-fluoro-derivatives, 16,16-difluoro-derivatives, 17S-methyl-derivatives, 17R,S-fluoro-derivatives, 17,17-difluoro-derivatives, 19-methyl-derivatives, 20-methyl-derivatives, 20-ethyl-derivatives, 19-desmethyl-derivatives, 16-desbutyl-16-phenoxy-derivatives and 2-decarboxy-2-carboxy
  • a keto-hemiacetal equilibrium may sometimes be formed by the formation of a hemiacetal between the hydroxy group at 11-position and the keto group at 15-position.
  • the ratio of the existing isomers will vary depending on the structure of other part of the molecule or the kind of possible substituents and in some cases one of the isomers is predominantly present.
  • the present invention includes both isomers, and while any compound of the invention may be represented by a structure or nomenclature of keto-type, this should be understood as a matter of mere convenience and should not be considered to be intended to exclude the compound in hemiacetal type isomer.
  • indivisional tautomeric isomers a mixture thereof, or optical isomers, a mixture thereof, racemic mixture and other isomers such as stereoisomers can be used in the some purpose.
  • Some of the compounds used in the present invention are novel and may be prepared by the method disclosed in Japanese Patent Publications A-64-52753, A-1-104040, A-1-151519, A-2-131446 etc. Alternatively, these compounds may be prepared by a process analogous to that described herein or to known process.
  • a practical preparation of the 15-keto compounds involves the following steps; referring to the Synthetic Charts I to III, reaction of the aldehyde (2) prepared by the Collins oxidation of commercially available (-)-Corey lactone (1) with dimethyl (2-oxoheptyl)phosphate anion to give ⁇ , ⁇ -unsaturated ketone (3), reduction of the ⁇ , ⁇ -unsaturated ketone (3) to the corresponding saturated ketone (4), protection of the carbonyl group of the ketone (4) with a diol to the corresponding ketal (5), and deprotection of the p-phenylbenzoyl group to give the corresponding alcohol (6) followed by protection of the newly derived hydroxy group with dihydropyrane to give the corresponding tetrahydropyranyl ether (7).
  • a precursor of PGEs wherein ⁇ -chain is a 13,14-dihydro-15-keto-alkyl group is prepared.
  • 6-keto- PGE 1 s (15) of which a group constituted with carbon atoms at positions 5, 6 and 7 is --C 7 H 2 --C 6 (O)--C 5 H 2 --, may be prepared in the following steps; reduction of the tetrahydropyranyl ether (7) with, for example, diisobutyl aluminum hydride to give the corresponding lactol (8), reaction of the lactol (8), with the ylide generated from (4-carboxybutyl)triphenyl phosphonium bromide followed by esterification (10), cyclization between the 5,6-double bond and the hydroxyl group at 9-position with NBS or iodine to give the halogenated compound (11), dehydrohalogenation of the compound (11) with, for example, DBU to give the 6-keto compound (13) followed by Jones oxidation and removal of the protecting groups.
  • PGE 2 s (19) of which a group constituted with carbon atoms positions 5, 6 and 7 is --C 7 H 2 --C 6 H ⁇ C 5 H-- may be prepared in the following steps; as shown in the Synthetic Chart II, reduction of the above tetrahydropyranyl ether (7) to give the lactol (8), reaction of the resultant lactol (8) with the ylide derived from (4-carboxybutyl-)triphenyl phosphonium bromide to give the carboxylic acid (16) followed by esterification to give ester (17), Jones oxidation of the esters (17) to give the compound (18), and removal of the protecting groups.
  • the compound having --C 7 H 2 --C 6 H 2 --C 5 H 2 -- may be prepared by using the same process as that for preparing PGE 2 having --CH 2 CH ⁇ CH-- and subjecting the resultant compound (18) to catalytic reduction for reducing the double bond between the positions 5 and 6followed by removal of the protective groups.
  • Synthesis of 5 6-dehydro-PGE 2 s having --C 7 H 2 --C 6 .tbd.C 5 -- may be carried out by capturing a copper enolate formed by 1,4-addition of a monoalkylcopper complex or a dialkylcopper complex of the following formulae: ##STR5## wherein G is alkyl to 4R-t-butyldimethylsilyloxy-2-cyclopenten-1-one with 6-alkoxycarbonyl-1-iodo-2-hexyne or the derivatives.
  • the 11 ⁇ type PGEs can be prepared according to the Synthetic Chart III.
  • PGE derivatives having methyl group at position 11 in place of hydroxy can be prepared by reacting a dimethyl copper complex with PGA-type compound obtained by subjecting 9-hydroxy-11-tosylate to the Jones oxidation.
  • they can be prepared by protecting carbonyl of saturated ketone (4) produced by reduced by reducing unsaturated ketone (3), eliminating p-phenylbenzoyl and tosylating the produced alcohol, treating with DBU to form a lactol, introducing the alpha-chain by Wittig reaction, oxidizing the alcohol at 9-position to give PGA-type compound, and reacting the product with dimethyl copper complex in order to introduce a methyl group into position 11 to give 11-methyl-PGE-type compound, which on reduction with e.g.
  • 11-methyl-PGF-type compound is obtained by a benzophenone-sensitized photoaddition of methanol of PGA-type compound, which is reduced with e.g. sodium borohydride to give 11-hydroxymethyl-PGF-type compound.
  • the 16-mono- or 16,16- di-halo type PGEs can be prepared according to the Synthetic Chart IV.
  • the synthetic route for the compounds used in the present invention is not limited to the above one and may vary using different protecting, reducing and/or oxidizating methods.
  • novel compounds of the formula III may be prepared by the following process, as summarized in Synthetic Charts V to VII, wherein P1, P2, P3, P4, P5, P6, P7, P8, Pa, Pb, Pc and Pd are protective groups, R'a is lower alkyl and Rb and Rc are the same as above.
  • a protected Corey lactone (40) (commercially available) having a suitable protective group (e.g. 4-phenylbenzoyl) is oxidized (e.g. by Collins oxidation) and the produced aldehyde (41) is reacted with (2-oxoalkyl) phosphonic acid ester having desired R2 and R3 groups to give the compound (42).
  • the oxo group is reduced to form (43), which is converted into (44) by protecting reaction.
  • the acyl group at position 11 is removed to produce (45), to which another protective group (e.g. tetrahydropyramyl) is introduced to give (46).
  • the lactone ring is opened with alkali to form a carboxylic acid which, on esterification, gives (47).
  • a protective group e.g. tetrahydropyranyl
  • the ester group by a reducing agent (e.g. by isobutylaluminum hydride) into an aldehyde group
  • the produced compound is reacted with an ⁇ -chain introducing agent (f) in the presence of a basic condensing agent (e.g. litium isopropyl amide) to form (49), of which the terminal group in ⁇ -chain is deprotected to produce (50).
  • the obtained alcohol is oxidized (e.g.
  • the ⁇ -chain introducing agent (f) is prepared by a process shown in Synthetic Chart V.
  • E-caprolactone (a) is ring-opened by an alcohol which can form the carboxy protective group Pa to give (b).
  • the hydroxy group is protected to give (c), which is decarboxylated to (d), halogenated to (e) and then subjected to halogen exchange reaction to afford the compound (f).
  • the protected Corey lactone (40) is converted into the compound (59) by reaction steps similar to that from (1) to (7) in synthetic Chart I.
  • the compound (59) is hydrolyzed by alkali (e.g. sodium or potassium hydroxide) to form the free acid (60), which is esterified (e.g. with diazomethane) to give (61).
  • alkali e.g. sodium or potassium hydroxide
  • esterified e.g. with diazomethane
  • the ester group is reduced (e.g. by lithium aluminum hydride) to produce an alcohol (63) and newly formed hydroxy group is oxidized (e.g. by Swan oxidation) to an aldehyde (64).
  • the aldehyde is reacted with an ⁇ -chain introducing agent (i) in the presence of zinc dust and mercuric chloride under ultrasonic irradiation to produce the compound (65).
  • This is deprotected to form (66) and hydrogenated (e.g. over Pd/C) to afford (67), which is then oxidized in two steps (e.g. swan oxidation and Jone's oxidation), via(68), to give (69).
  • the acid (69) is deprotected either directly to (71) or via ester (70) to (72).
  • the ⁇ -chain introducing agent (i) is prepared by a process shown is synthetic Chart VIII.
  • the acetylenic alcohol (g) is protected to form (h), which is reacted with difromodifluoromethane to produce (i).
  • the compound (73) (for example, a compound wherein Q 1 ' and Q 2 ' are hydrogen is the compound 8 described in Synthetic Chart I on page 37 of JP-A-52753/1989) is reacted with a ylid produced from (6-carboxyhexyl)triphenylphosphonium bromide to form the compound (74), which is esterified to give the compound (75), which, on removal of the protective groups, can give the compound (76).
  • the above compound (75) is oxidized by Jones oxidation to form the compound (77), which can be given the compound (78) by removing the protective groups.
  • the compounds wherein W is --CH ⁇ CH--CH 2 -- or --CH 2 --CH ⁇ CH-- can be prepared by reacting the compound (73) with a ylid produced from (6-carboxy-2-hexenyl)triphenylphosphonium bromide or (6-carboxy-3-hexenyl)triphenylphosphonium bromide, respectively, and the treating the formed compound in a manner similar to that above.
  • the compound (80) obtained by deprotecting the compound (79) which is commercially available, is oxidized by Swern oxidation to give the aldehyde (81), which is reacted with 2-oxoheptyl phosphonate (for example, 3,3-dihalogenated derivative) to give the compound (82). Catalytic reduction of it gives the compound (83), the ketone moiety of which is reduced by sodium borohydride to form the compound (84). This is further reduced by diisobutylaluminum hydride to give the lactol (85).
  • the lactone moiety in the compound obtained by removing the protective group at position 11 and introducing a protective group in position 15 of the compound (84) is reduced to lactol and then an ⁇ -chain is introduced to the product by Wittig reaction. Then the hydroxy group at position 11 is protected by a lower alkane- or monocyclic aryl-sulfonate group and the product is subjected to oxidation (for example, Jones) to give 10-en-9-one compound, which is reacted with lower alkyl lithium to form a 11-lower alkyl compound.
  • oxidation for example, Jones
  • Compounds of PGD-type can be obtained by oxidizing the 11-deprotected compounds.
  • Compounds of PGA-type can be obtained from the 10-en-9-one compounds.
  • 6-keto compounds can be obtained by reacting the compound (75) with N-bromosuccinimide or iodine to form the compound (93), followed by treatment with DBU.
  • the 5,6-dehydro (i.e. acetylenic) compounds can be prepared, according to Synthetic Chart X, by reacting the copper enolate, formed by reacting the compound (95) with a copper complex, with 8-alkoxycarbonyl-1-iodo-2-octyne.
  • Saturated ⁇ -chain introducing agent are prepared as shown in Synthetic Chart XI.
  • the hydroxy group at position 15 of the compound (84) is protected (for example, by silyl protective group) to form the compound (97) and lactone moiety of which is reduced to lactol giving the compound (98), which is then reacted with an ⁇ -chain introducing agent (for example, a ylid produced from (6-carboxyhexyl)triphenyl phosphonium bromide) to give the compound (99).
  • an ⁇ -chain introducing agent for example, a ylid produced from (6-carboxyhexyl)triphenyl phosphonium bromide
  • the protective group at position 15 is removed to give the compound (101), which is oxidized to the compound (102). Deprotection at positions 9 and 11 gives the desired compound (104).
  • the above 15-keto-PG compounds have action inhibiting inflammatory reaction, they are useful in treatment of inflammatory diseases. Such activities can be measured by the standard methods, for example, methods using experimental inflammatory disease model.
  • the compounds used in the present invention may be used as a medicine for animals and human beings and usually applied systemically or locally by the method of oral administration, intravenous injection (including instillation), subcutaneous injection, rectal administration and the like. While the dosage will vary depending on the animal or human patient, age, body weight, symptom to be treated, desired therapeutic effect, administration route, term of treatment and the like, satisfactory effects will be obtained with the dosage of 0.01-100 ⁇ g/eye administered locally (i.e. ocularly) or 0.001-500 mg/kg administered in 2 to 4 divided doses a day or as a sustained form.
  • solid composition of this invention for oral administration, tablets, torches, buccals, capsule, pills, powders, granules and the like are included.
  • the solid composition containing one or more active substances is mixed with at least an inactive diluent such as lactose, mannitol, glucose, hydoxypropyl cellulose, micro crystalline cellulose, starch, polyvinyl pyrolidone, magnesium aluminate metasilicate.
  • the composition may contain additives other than the inactive diluent, such as lubricants e.g., magnesium stearate, a disintegrator e.g. cellulose calcium gluconates, stabilizers e.g.
  • ⁇ , ⁇ - or ⁇ -cyclodextrins etherated cyclodextrins (e.g. dimethyl- ⁇ -, dimethyl- ⁇ -, trimethyl- ⁇ -, or hydroxypropyl- ⁇ -cyclodextrins), branched cyclodextrins (e.g. glucosyl- or maltosyl-cyclodextrins), formyl cyclodextrins, sulfur-containing cyclodextrins, misoprotols or phospholipids.
  • cyclodextrins may form complex to increase the stability of the compounds. The stability may be often increased by forming lyposome with phospholipids.
  • Tablets and pills may be coated with an enteric or gastroenteric film such as white sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalates and the like, if necessary, and furthermore they may be covered with two or more layers. Additionally, the composition may be in the form of capsules made of substance easily absorbed such as gelatin. Further, when rapid effect is required, it may be in the form of buccal, in which glycerol, lactose etc are used as a base.
  • enteric or gastroenteric film such as white sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalates and the like, if necessary, and furthermore they may be covered with two or more layers. Additionally, the composition may be in the form of capsules made of substance easily absorbed such as gelatin. Further, when rapid effect is required, it may be in the form of buccal, in which glycerol, lactose etc are used as a base.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contain a generally used inactive diluent such as purified water or ethyl alcohol.
  • the composition may contain additives such as wetting agents, suspending agents, sweeteners, flavors, perfumes and preservatives.
  • compositions for oral administration may be sprays which contain one or more active substance and can be prepared according to a well known method.
  • the injection of this invention for non-oral administration includes serile aqueous or nonaqueous solutions, suspensions, and emulsions.
  • Diluents for the aqueous solution or suspension include, for example, distilled water for injection, physiological saline and Ringer's solution.
  • Diluents for the nonaqueous solution and suspension include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and polysorbates.
  • the composition may contain other additives such as preservatives, wetting agents, emulsifying agents, dispersing agents and the like. These are sterilized by filtration through, e.g. a bacteria-retaining filter, compounding with a sterilizer, gas sterilization or radiation sterilization. These can also be prepared by producing a sterilized solid composition and dissolving in sterilized water or a sterilized solvent for injection before use.
  • composition according to the present invention is the rectal or vaginal suppository.
  • This can be prepared by mixing at least one active compound according to the invention with a suppository base which may be softened at body temperature, optionally containing non-ion surfactant having appropriate softening temperature for improving absorption.
  • Collins reagent was prepared by using chromic anhydride (13.5 g) and pyridine (21.8 ml) in dichloromethane (300 ml), and to this were added Celite (40 g) and (15RS)-16,16-difluoro-13,14-dihydro-11-O-tetrahydropyranyl-PGF 2 .alpha. benzyl ester (36) (2.550 g).
  • the reaction mixture was treated in the conventional manner and the crude product was purified by silica-gel column chromatography to give the title compound (37). Yield: 1.991 g (78.6%).
  • reaction mixture was treated in the conventional manner and the obtained crude product was subjected to the column chromatography to give the title compound (43) as a mixture of the diastereomers.
  • reaction mixture was treated in the conventional manner and the obtained crude product was subjected to the silica gel column chromatography to give the title compound (44) as a mixture of the diastereomers.
  • Methyl 2(RS)- ⁇ 2-[(1R,2R,3R,5S)-2-[(E)-3(RS)-t-butyldimethylsilyloxy-1-octenyl]-3,5-bis-tetrahydropyranyloxycyclopentyl]-1(RS)-hydroxyethyl ⁇ -2(SR)-fluoro-6-hydroxyhexanoate (50) (1.23g) was subjected to Collins oxidation at -50° C. under an argon atmosphere for 4.5 hours.
  • the crude product obtained in the conventional manner was dissolved into ether, and a solution of diazomethane in ether was added thereto. The resultant mixture is stirred at room temperature for 1 hour.
  • Methyl 5(RS)-fluoro-6-oxo-7- ⁇ (1R,2R,3R,5S)-2-[3-oxo-octyl]-3,5-bis-tetra-hydropyranyloxy-cyclopentyl ⁇ -6-oxo-heptanoate (0.24 g) was dissolved into a mixed solvent of acetic acid, tetrahydrofuran and water (3:1:1), and the resultant mixture was stirred at 45° C. for 4.5 hours.
  • the crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give a diol product (56) (0.15 g).
  • the monosilyl product (0.135 g) was subjected to Collins oxidation in methylene chloride at room temperature for 15 minutes.
  • the crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (57).
  • Corey-lactone (40) (10.0 g) dissolved in dichloromethane (160 ml) was subjected to Moffatt oxidation using DMSO (79.2 g), dicyclohexylcarbodiimide (24.0 g), pyridine (2.3 ml) and trifluoroacetic acid (1.1 ml) to give Corey-lactone aldehyde (2a).
  • dimethyl (2-oxoheptyl)phosphonate anion was prepared from dimethyl-(2-oxoheptyl)phosphonate (6.31 g) and sodium hydride (60%, 0.13 g) in dichloromethane, and the solution of the previously obtained aldehyde (160 ml) was added dropwise thereto, and the resultant mixture was stirred at room temperature for 11.5 hours.
  • the crude product obtained by treating in the conventional manner was subjected to silica gel chromatography to give the title compound (42).
  • the triol (66) was subjected to catalytic hydrogenation over 5% Pd/C (0.06 g) in ethyl acetate (50 ml).
  • the reaction mixture was treated in the conventional manner and the obtained crude product was subjected to silica gel chromatography to give the title compound (67).
  • the obtained diketoaldehyde (68) (0.212 g) was subjected to Jones oxidation using Jones reagent (2.67M 153.6 ⁇ ) at a temperature between -50° C. and -40° C. to give the carboxylic acid (69), which was reacted with diazomethane in order to obtain methyl ester.
  • the obtained crude product was subjected to silica gel column chromatography to give the title compound (70).
  • the compound (74) (1.68 g) was esterified in the conventional procedure with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, 0.78 ml) and isopropyl iodide (0.35 ml) in acetonitrile (15 ml). The residue was subjected to silicagel column chromatography to give the titled compound (75). Yield: 0.908 g (88%).
  • the compound (75) (0.305 g) was dissolved in a mixed solvent (6 ml) consisting of acetic acid, THF and water (2:1:1) and kept at 50° C. for 14 hours.
  • the resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (76). Yield: 0.213 g (90%).
  • Oxalyl chloride (2M, 0.45 ml) and DMSO (0.13 ml) were added to dichloromethane (5 ml) cooled previously to -70° C. and the resultant mixture was stirred for 15 hours.
  • the compound (77) (0.311 g) was dissolved in a mixed solvent (5 ml) consisting of acetic acid, THF and water (2:1:1) and kept at 50° C. for 3 hours. The resultant mixture was worked up with the conventional procedure and the residue was subjected to silicagel column chromatography to give the titled compound (78). Yield: 0.156 g (66%).
  • the compound (82) (12.7 g) was catalytically hydrogenated over 5% palladium on carbon (catalytic amount) in ethyl acetate (300 ml) under hydrogen atmosphere to give the titled compound (83). Yield: 12.5 g (99%).
  • the compound (88) (0.514 g) was dissolved in a mixed solvent (30 ml) consisting of acetic acid, THF and water (4:2:1) and the solution was kept overnight at the room temperature.
  • the resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (78 ). Yield: 0.272 g (61%).
  • the compound (91) (0.288 g) was dissolved in a mixed solvent (30 ml) consisting of acetic acid, water and THF (4:2:1) and the solution was kept at 45° C. for 3.5 hours.
  • the resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (92). Yield: 0.184 g (76%).
  • the compound (75) obtained in Preparation Example 3 is dissolved in a mixture of anhydrous tetrahydrofuran and anhydrous methylenechloride. A small excess amount of N-bromosuccinimide is added to the Solution at 0° C. and the resultant mixture is stirred for 5 minutes. The resultant mixture is worked up with the conventional procedure and the crude product is subjected to column chromatography to give the compound (93) (Q 1 ' ⁇ Q 2 ' ⁇ H, Rb'-Rc' ⁇ butyl, P 1 ⁇ tetrahydroxypyranyl, P 2 ⁇ ethylene, P 3 ⁇ isopropyl). This is dissolved in anhydrous toluene. The solution is treated with DBU and stirred overnight at 40° C.
  • Tert-butyl lithium is added dropwise to a solution of 8-methoxy-3,3-ethylenedioxy-1-iodooctane (prepared according to JP-A-52753/1989) in ether at -78° C. over 30 minutes and the resultant mixture is stirred for 3 hours. Then a solution, cooled to -78° C., of cuprous iodide and tributylphosphine in ether is added to the above mixture in one portion and the resultant mixture is stirred for 20 minutes to form the complex (j). A solution of 4R-tertbutyldimethylsililoxy-2-cyclopenten-1-one (95) in tetrahydrofuran is added dropwise to the mixture over 95 minutes.
  • a ylid was prepared from sodium hydride (60%, 0.934 g), DMSO (25 ml) and (6-carboxyhexyl)triphenylphosphonium bromide (5.50 g) in the conventional procedure.
  • the ylid was added to a solution of the compound (98)in ether (8 ml) and the resultant mixture was stirred at the room temperature for 2 hours.
  • the resultant mixture was worked with the conventional procedure to give the carboxylic acid (99), which was treated with diazomethane.
  • the product was subjected to silicagel column chromatography to give the titled compound (100). Yield: 0.43 g (48%).
  • the compound (100) (0.438 g) was converted to ditetrahydropyranyl ether using an excess amount of dihydropyran and a catalytic amount of p-toluenesulfonic acid in dichloromethane (25 ml). The resultant mixture was subjected to silicagel column chromatography to give the compound (101). Yield: 0.494 g (99%).
  • the compound (102) (0.284 g) was subjected to Swern oxidation using oxalyl chloride (0.165 ml) and DMSO (0.3 ml) in dichloromethane (10 ml). The product was subjected to silicagel column chromatography to give the compound (103). Yield: 0.251 g (89%).
  • the compound (103) was dissolved in a mixed solvent (30 ml) consisting of acetic acid, water and THF (4:2:1) and the solution was kept at 45° to 50° C. for 3 hours.
  • the resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (104). Yield: 0.137 (76%).
  • the compound (88) (0.181 g) was dissolved in a mixed solvent (25 ml) consisting of acetic acid, water and THF (4:2:1) and the solution was kept at 45° C. for 3.5 hours.
  • the resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (78). Yield: 0.140 g (91%).
  • the active ingredient can be replaced by any other compound within the compounds used in the invention.
  • mice Male Wistar rats (weight: about 120 g) were used as the test animals. The animals were allotted to groups, each consisting of 10 animals (20 eyes). Fifteen minutes after the administration of a test compound, 0.05 ml of 1% carrageenan in physiological saline was injected subconjunctivally at an upper eyelid of the animals through a microsyringe to induce an edema. After 4 hours, the animals were sacrificed by vertebral cervial dislocation. Parts of conjunctive showing inflammation was cut off and separately weighed. The test compound was dissolved in the physiological saline and administered ocularly (5 ⁇ l/eye). The control received the physiological saline.
  • Test Example 2 The procedure of Test Example 1 was repeated except that 13,14-dihydro-15-keto-16,16-difluoro-PGE 2 (Test Compound 2) was used as the test compound. In addition, results after subcutaneous administration (5 ml/kg) were observed. The results are shown in Tables 2 and 3.
  • mice Male Wistar rats (weight: about 120 g) were used as the test animals. The animals were allotted to groups, each consisting of 10 animals (20 eyes). Two minutes after the administration of test compounds, 0.5% Evans Blue in physiological saline (0.5 ml) was injected in the caudal vein to elicit the PCA reaction. Immediately after, 0.1% histamine hydrochloride in physiological saline (50 ⁇ l) was injected subconjunctivally at an upper eyelid. After 30 minutes, the animals were sacrificed by vertebral cervial dislocation and the scalp was peeled away towards the eyelid. Part of skin and conjunctive showing inflammation was cut off and weighed.
  • said conjunctive was minced and extracted overnight with 4 ml formaldehyde at 40° C. with shaking.
  • the dye in the conjunctive was assayed by measuring absorption of the extract at 625 nm.
  • the test compounds were dissolved in the physiological saline and administered ocularly (5 ⁇ l/eye). The control received the physiological saline.
  • Test Example 3 The procedure of Test Example 3 was repeated except that Test Compound 1 (see: Test Example 1) as the test compound and 10 ⁇ l of 0.1% histamine hydrochloride in physiological saline were used. The results are shown in
  • test compounds have an activity inhibiting experimental conjunctivitis.

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CN102126998B (zh) * 1996-06-10 2013-06-12 苏坎波公司 内皮素拮抗剂
US6197821B1 (en) 1997-11-28 2001-03-06 R-Tech Ueno, Ltd. Endothelin antagonist
US20030060511A1 (en) * 2001-08-23 2003-03-27 Sucampo Ag Method for treatment of ocular hypertension and glaucoma
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US20090082442A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched lubiprostone

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ATE137116T1 (de) 1996-05-15
EP0467564A3 (en) 1992-07-08
DE69118978D1 (de) 1996-05-30
JPH0532551A (ja) 1993-02-09
EP0467564A2 (en) 1992-01-22
CA2046069A1 (en) 1992-01-11
KR920002151A (ko) 1992-02-28
DE69118978T2 (de) 1996-11-14
DK0467564T3 (da) 1996-05-13
GR3019760T3 (en) 1996-07-31
JP2562239B2 (ja) 1996-12-11
KR100195430B1 (ko) 1999-06-15
CA2046069C (en) 2002-04-09
EP0467564B1 (en) 1996-04-24
ES2089136T3 (es) 1996-10-01

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